Risk factors for ARDS often include conditions which compromise intestinal perfusion and viability (sepsis, shock, multiple organ failure). Since intestines have high concentrations of potential toxins, we hypothesize that intestinal ischemia/reperfusion (I/R) injury causes acute edematous lung injury (ARDS) by a mechanism involving release of XO into the circulation. Our preliminary data supports our premise. First, circulating XO increases after reperfusion of the ischemic rat and canine intestines and plasma XO levels are higher in humans with ARDS than controls. Second, lung neutrophil sequestration occurs in the lungs of rats subjected to intestinal I/R. Similarly, increases in O2 metabolite release and neutrophil adherence to cultured endothelial cells (EC) are both decreased by XO inhibition. Third, skin burn increases blood XO levels and damages lungs in vivo and isolated blood-perfused lungs in untreated controls but not rats treated with XO inhibitors and O2 metabolite scavengers. My immediate specific objectives are to determine the contribution of XO- derived O2 metabolites to acute edematous lung injury following intestinal I/R and to relate this injury to changes in circulating XO and antiprotease levels, lung neutrophil accumulation and activation in parallel in vivo, isolated lung and in vitro test systems. The significance of this project is to provide new information about the mechanisms by which blood-borne mediators are formed and contribute to lung injury. The approach may reveal common mechanisms which unify acute lung injury from diverse causes, further targeting treatment. Lance S. Terada, M.D. is a broad certified internist and is committed to a career in academic medicine and research. He has complete his training in clinical pulmonary medicine and has spent the last 15 months investigating basic mechanisms of oxidant injury under John E. Repine, M.D. Dr. Repine has extensive experience in training young investigator and has a well equipped laboratory.